Central mu- and kappa-opioid agonists evoke profound changes in urine flow rate and urinary sodium excretion via multiple integrated neural and physiological mechanisms. In addition to these subtypes, a novel opioid-like peptide, nociceptin, and opioid receptor, the ORL1 receptor, have recently been identified. Despite their structural resemblance to endogenous opioid peptides and receptors, the role of nociceptin and the ORL1 receptor in the regulation of renal function, is not known. The studies outlined in this proposal are designed to test the hypothesis that the endogenous central nociceptin peptide system plays a physiological role in the renal handling of water and sodium via mechanisms that interact with central mu- and kappa-opioid renal regulatory mechanisms. These studies will utilize methods for measurements of changes in cardiovascular and renal function in conscious rodents, and in vivo molecular biology techniques (antisense oligodeoxynucleotide), to study the role of a novel endogenous opioid peptide-like system in the central regulation of renal function. These studies will also determine how the nociceptin system interacts with central mu- and kappa-opioid systems in the renal handling of water and sodium. The Specific Aims are: 1) to characterize the changes in renal hemodynamics and excretory function produced by intra-cerebroventricular (ICV), or paraventricular (PVN) microinjection of nociceptin; 2) t0 determine the role of the renal sympathetic nerves and 3) vasopressin, in these renal responses; 4) determine the receptor pathway by which ICV or PVN nociceptin mediated its renal responses; 5) determine whether endogenous central mu- or kappa-opioid systems modulate the renal responses produced by ICV nociceptin; 6) establish whether endogenous central nociceptin systems modulate the renal responses produced by central administration of selective mu- or kappa-opioids; and 7) determine the contribution of the endogenous central mu-, kappa- and nociceptin systems to the renal responses produced by an integrated physiological stimuli. Completion of these studies will provide important information on a novel opioid system involved in the central neural control of renal function, and determine how this system may interact with classical opioid systems in this regulatory process.